A. Characteristics

1. Formerlly called Pneumocystis carinii
2. Fungal organism previously classified as a parasite
3. Over 50 strains colonize respiratory tract and can cause disease in humans
4. Low virulence pathogen widely distributed in nature
5. Humans have universal exposure as children to P. jiroveci
6. Nonpathogen in the absence of immunosuppression
7. Clinical Settings
   1. Most commonly seen in HIV infected patients with CD4 <250/µL [6]
   2. Also seen in patients on (chronic) glucocorticoids [3]
   3. Increased incidence in stem cell/marrow transplants
   4. Also in solid tumor patients on high dose chemotherapy

B. Disease Spectrum and Symptoms

1. Mainly causes pulmonary infections with diffuse pneumonia
   1. Most common symptoms are shortness of breath and fever
   2. Cough is variable, with variable sputum production
2. Disease much more serious in non-HIV infected persons
   1. Highly inflammatory immune response leads to increased symptoms
   2. In HIV infected persons, high organism burden with relatively low neutrophil levels
   3. In non-HIV infection, higher neutrophil and inflammation levels, lower organism burden
   4. Large numbers of neutrophils can lead to exacerbation in symptoms
3. Extrapulmonary disease usually in spleen and/or liver
   1. Fungemia with septic symptoms may occur
   2. High fevers, abdominal pain
4. Aerosolized pentamidine prophylaxis increases risk for extrapulmonary disease

C. Diagnosis

1. High clinical suspicion required:
   1. HIV+ patients, particularly with CD4+ T cells <200/µL
   2. Patients on glucocorticoids or other immunosuppressives
   3. PCP most common in immunosuppressed patients with dosages raised or lowered
2. Usually presents as acute, diffuse interstitial pneumonia on chest radiograph (CXR)
   1. However, may present with any abnormality on CXR
   2. For example, upper lobar PCP is not uncommon in patients on pentamidine prophylaxis
3. Induced sputum or Bronchoalveolar Lavage (BAL) for analysis
   1. Induced sputum with nebulized saline is standard specimen
   2. Induced sputum more sensitive in HIV+ patients due to higher organism counts
   3. Immunofluorescent stained smear of induced sputum is performed
   4. Polymerase chain reaction (PCR) on induced sputum is most sensitive
   5. Lung biopsies are very infrequently used
   6. PCR on oral washes may have up to 80% sensitivity
4. Serum LDH elevation: highly sensitive, non-specific for PCP
5. High A-a gradient (>10mm): insensitive and nonspecific

D. Therapeutic Overview [1,2]

1. Therapeutic Options
   1. Selection usually depends on severity of disease and comorbid conditions
   2. Many patients develop allergies or other intolerance to one or more of these agents
   3. Side effects / reactions must be monitored closely
2. Trimethoprim-Sulfamethoxazole (TMP-SMX, Bactrim®)
   1. Most effective drug; may be given intravenously or orally
   2. Of all agents, poorest tolerability in HIV+ patients
3. Pentamidine
4. Clindamycin + Primaquine
5. Atovaquone (Mepron®)
6. Dapsone + trimethoprim
7. Trimetrexate + folinic acid (leukovorin)

E. Therapy [1,4]

1. Moderate and Severe Diseaes
   1. First Choice: TMP-SMX 15-20/75-100 mg/kg/day IV divided q6-8 hours with fluids
   2. For pO2<50-70mm: add prednisone 40mg bid (or methylprednisolone) for 5 days
   3. Glucocorticoids are then tapered by 50% every 5 days for total duration 21 days
   4. Consider adding pentamidine 3-4 mg/kg/day im or IV to TMP/SMX
   5. Alternative first line is Pentamidine 4mg/kg IV daily OR
   6. Clindamycin 600mg IV q8 hours + primaquine 15mg base qd
   7. Alternative: trimetrexate 45mg/m2/d with folinic acid 20mg/m2 q6 hours
   8. If patient fails to respond to therapy, consider possibility of multiple pathogens
   9. May require intubation
2. Mild Disease
   1. TMP-SMX - oral high dose, 2 Bactrim DS tabs po tid-qid
   2. Clindamycin 600mg po tid + Primaquine 30mg base po qd also very effective
   3. Atovaquone (Mepron®) 750mg po tid suspension is alternative
   4. Dapsone 100mg po qd with Trimethoprim (TMP) 200-400mg po tid
   5. Trimetrexate (NeuTrexin®) - qd injections with leucovorin, 21 days, 45mg/m2
   6. Pentamidine 600mg daily aerosol can be used

F. Prophylaxis [4,5]

1. Given to all patients with CD4 <200/µL OR history of PCP at CD4>200/µL
   1. Prophylaxis should be maintained as long as CD4 counts are <200/µL
   2. HIV+ patients on antiretroviral therapy with CD4>200/µL can discontinue (see below)
2. Overview of Prophylactic Agents
   1. TMP/SMX - always first line
   2. Dapsone ± pyrimethamine (+leukovoron)
   3. Aerosolized pentamidine
   4. Atovaquone
   5. TMP/SMX is consistently the most effective regimen [5]
3. TMP/SMX (Bactrim®, Septra®)
   1. Standard is 1 SS (single strength) po qd or one DS (double strength) 3 times/week
   2. TMP/SMX also effective for toxoplasmososis prophylaxis [2,7]
   3. Overall, TMP/SMX most effective but with poorest tolerability [5,8,11]
   4. TMP/SMX prophylaxis risk-benefit is $16,000 per quality-adjusted life year (QALY) [9]
   5. TMP/SMX allergies are common in HIV infected patients (50-100X general population)
   6. Safe and effective TMP/SMX desensitization in HIV is possible with escalating doses [18]
   7. Sulfa-drug resistant PCP documented but clinical effects not seen
   8. Resistance due to mutations in dihydropteroate synthase
4. Dapsone
   1. Given with pyrimethamine to if toxoplasmosis seropositive [2,7]
   2. G6PD levels should be checked before using dapsone or pyrimethamine
   3. Patients with G6PD deficiency will develop severe anemia on dapsone or pyramethamine
   4. Not as effective as TMP/SMX, with ~18 cases of pneumocystis per 100 person-years [11]
   5. Dose is 50mg bid or 100mg qd po OR 200mg po qweek
   6. May be given with pyrimethamine 50mg qweek po and leucovorin 25mg qweek po
5. Atovaquone (Mepron®; second line) [11]
   1. For use in patients intolerant to TMP/SMX
   2. At least as effective for prophylaxis as dapsone
   3. Should certainly be used in patients with G6PD deficiency
   4. Not as effective as TMP/SMX, with ~16 cases of pneumocystis per 100 person-years
   5. Dose is 1500mg suspension qd
6. Pentamidine 300mg aerosolized, q month (third line prophylaxis)
7. Despite prophylaxis, PCP occurs in ~15% of patients with CD4<75/µL over 2 years [10]
8. Azithromycin 1200mg po each week reduced incidence of pneumocystis infection by 45% in AIDS patients with MAI already taking PCP prophylaxis [7]
9. Discontinuation of PCP prophylaxis
   1. Prophylaxis for primary PCP can be discontinued in HIV+ patients treated with highly active antiretroviral therapy (HAART) with CD4 counts >200/µL [12,13,14,16]
   2. Discontinuation is safe in secondary prophylaxis patients provided CD4<200/µL [16,17]

References

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3. Lionakis MS and Kontoyiannis DP. 2003. Lancet. 362(9398):1828
4. Pneumocystis carinii. 1995. Med Let. 37(959):87
5. Ioannidis JPA, Cappelleri JC, Skolnik PR, et al. 1996. Arch Intern Med. 156(2):177
6. Huang L, Quartin A, Jones D, Havlir DV. 2006. NEJM. 355(2):173
7. Schacker T, Collier AC, Hughes J, et al. 1996. Ann Intern Med. 125(4):257
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17. Ledergerber B, Mocroft A, Reiss P, et al. 2001. NEJM. 344(3):168
18. Demoly P, Messaad D, Sahla H, et al. 1998. J Allergy Clin Immunol. 102:1033
19. Kovacs JA, Gill VJ, Meshnick S, Masur H. 2001. JAMA. 286(19):2450